| Description | PF-04859989 HCl is a brain-penetrable and irreversible inhibitor of kynurenine amino transferase II (KAT II), which is the enzyme responsible for most of the brain synthesis of kynurenic acid. |
| In vitro | The IC50s values are 23 and 263 nM for hKAT II and rKAT II. PF-04859989 HCl is selective for KAT II over human KAT I, KAT III, and KAT IV (IC50s of 22, 11, and >50 μM, respectively)[3]. |
| In vivo | Acute administration of the KAT II inhibitor PF-04859989 (5 or 10 mg/kg) was associated with a short-onset, time-dependent decrease in firing rate and burst activity of DA neurons, both parameters reaching a 50% reduction within 45 min. Furthermore, PF-04859989 reduced the number of spontaneously active DA cells as measured 4-6 after administration. Pretreatment with d-cycloserine (30 mg/kg) or CGP-52432 (10 mg/kg) prevented the inhibitory action of PF-04859989 (5 mg/kg) on firing rate and burst firing activity. In contrast, pretreatment with methyllycaconitine (MLA, 4 mg/kg) did not change the response, whereas picrotoxin (4.5 mg/kg) partially prevented the inhibitory effects of PF-04859989 (5 mg/kg, i.v.)[2]. |
| Target activity | KAT II:23 nM(human), KAT II:263 nM(rat), KAT I:22 μM, KAT IV:>50 μM, KAT III:11 μM |
| Synonyms | PF 04859989, PF04859989, PF-04859989HCl, PF-04859989 |
| molecular weight | 214.65 |
| Molecular formula | C9H11ClN2O2 |
| CAS | 177943-33-8 |
| Storage | Powder: -20°C for 3 years | In solvent: -80°C for 1 year | Shipping with blue ice. |
| Solubility | DMSO: 100 mg/mL (465.87 mM) H2O: 100 mg/mL (465.87 mM) |
| References | 1. Nematollahi A, Sun G, Jayawickrama GS, Hanrahan JR, Church WB. Study of the Activity and Possible Mechanism of Action of a Reversible Inhibitor of Recombinant Human KAT-2: A Promising Lead in Neurodegenerative and Cognitive Disorders. Molecules. 2016 Jun 29;21(7). pii: E856. doi: 10.3390/molecules21070856. PubMed PMID: 27367665. 2. Linderholm KR, Alm MT, Larsson MK, Olsson SK, Goiny M, Hajos M, Erhardt S, Engberg G. Inhibition of kynurenine aminotransferase II reduces activity of midbrain dopamine neurons. Neuropharmacology. 2016 Mar;102:42-7. doi: 10.1016/j.neuropharm.2015.10.028. Epub 2015 Oct 24. PubMed PMID: 26514401. 3. Kozak R, Campbell BM, Strick CA, Horner W, Hoffmann WE, Kiss T, Chapin DS, McGinnis D, Abbott AL, Roberts BM, Fonseca K, Guanowsky V, Young DA, Seymour PA, Dounay A, Hajos M, Williams GV, Castner SA. Reduction of brain kynurenic acid improves cognitive function. J Neurosci. 2014 Aug 6;34(32):10592-602. doi: 10.1523/JNEUROSCI.1107-14.2014. PubMed PMID: 25100593. 4. Koshy Cherian A, Gritton H, Johnson DE, Young D, Kozak R, Sarter M. A systemically-available kynurenine aminotransferase II (KAT II) inhibitor restores nicotine-evoked glutamatergic activity in the cortex of rats. Neuropharmacology. 2014 Jul;82:41-8. doi: 10.1016/j.neuropharm.2014.03.004. Epub 2014 Mar 16. PubMed PMID: 24647121; PubMed Central PMCID: PMC4372264. |
| Citations | 1. Liang X, Du W, Huang L, et al.Helicobacter pylori promotes gastric intestinal metaplasia through activation of IRF3-mediated kynurenine pathway.Cell Communication and Signaling.2023, 21(1): 1-14. |